Pancreas has endocrine glands (endocrine cells) and exocrine glands (exocrine cells), and is an organ playing an important role by the both cells. Exocrine cells mainly play a role of secreting digestive enzymes such as pancreatic lipase, trypsin, elastase, pancreatic amylase and the like.
Endocrine cells play a role of secreting pancreatic hormones, and it is known that glucagon is secreted from pancreatic α cells, insulin is secreted from pancreatic β cells, somatostatin is secreted from pancreatic δ cells, and pancreatic polypeptide (sometimes to be abbreviated as PP in the present specification) is secreted from PP cells. In recent years, it has been reported that ghrelin, which is a stomach-secreted hormone, is also secreted from pancreas.
Insulin plays an important role of promoting utilization of glucose, protein synthesis, and formation and storage of neutral fats, lowering blood glucose level, and maintaining blood glucose at a normal concentration. Pancreatic glucagon plays an important role, along with insulin, in a sugar metabolism regulatory mechanism, as a hyperglycemic hormone via hepatic glycogenolysis, gluconeogenesis action and the like. Somatostatin expresses an action by binding to a somatostatin receptor, and suppresses secretion of various hormones such as glucagon, insulin and the like in the pancreas. PP is a hormone secreted from the cells of islets of Langerhans in response to diet, known as a satiety factor, and reduces food ingestion and body weight gain. Ghrelin is known to stimulate food ingestion, and increase body weight gain by reducing fat oxidation.
Diabetes is a disease developed by insufficient insulin and loss of the function thereof, and difficult to cure once it is developed. Diabetes can be largely classified into two types of type I diabetes mellitus (insulin dependent diabetes) and type II diabetes mellitus (non-insulin dependent diabetes).
Type II diabetes mellitus is a chronic disease developed by resistance to insulin, which becomes problems in relation to lifestyle habits such as obesity due to overeating and inactivity, stress etc. Type II diabetes mellitus is often developed in middle-aged adults, and many of the diabetes patients are affected with this type diabetes.
Type I diabetes mellitus is a chronic disease caused by destruction of insulin-producing cells by autoimmune diseases, virus infection and the like to terminate secretion of insulin in the body. As a treatment method that can automatically control blood glucose level that continuously changes in the body and reduce burden on patients, pancreas transplantation or pancreatic islet transplantation is performed on patients with type I diabetes mellitus. While it is possible to achieve a normal blood glucose level by these treatment methods, the transplantation technique has not been sufficiently established, and the pancreas and pancreatic islet that can be transplanted are not sufficient. Moreover, to avoid immune rejection to a graft, the patients need to take an immunosuppressant for the entire life, and the problems of the risk of infection, side effects caused by immunosuppressant and the like still remain.
One of the treatment methods tried for type I diabetes mellitus is a method including reproducing an insulin-producing cell itself from the cells derived from the patient, and transplanting the cell into the body of the patient. According to this method, insulin can be produced in the body of the patient. In addition, since the cells are the patient's own cells, the method is also advantageous in terms of safety, since the problem of rejection can be resolved and the like.
Known methods for obtaining insulin-producing cells include a method of differentiating ES cells, a method of differentiating tissue stem cells of the pancreas of a patient, a method of isolating cells derived from the pancreatic duct epithelium of a patient out of body and differentiating the same and the like. Specifically, a method of inducing differentiation of pancreatic β cells from human ES cells by using activin and retinoic acid (RA) (patent document 1, non-patent documents 1-4), a method of inducing differentiation of glucagon-producing cells (α cells) from human ES cells (non-patent document 8), a method of inducing differentiation of pancreatic β cells from human iPS cells (non-patent documents 5-7), a method of efficiently inducing differentiation of insulin-producing cells, including introducing PDX1, which is known to be an important transcription factor involved in the development of the pancreas and also responsible for the development and function maintenance of insulin-producing cells, into ES cells, and cultivating the cells (patent document 2), and the like.
However, since the insulin-producing cells obtained by these methods show considerably low insulin production efficiency as compared to those of normal pancreatic β cells, the development of a method of efficiently obtaining insulin-producing cells that can be adopted for application of cell therapy is still required. Furthermore, it is desired to increase the number of obtainable cells to a practical level for the treatment of diabetes and the like.